Endo Exam 3: Sharma Anti-Obesity

What are the two hypothalamic centers that control feeding, and what neurons do they release?

The feeding (hunger) center in the lateral hypothalamic area releases NPY, AgRP, orexin, and MCH to stimulate feeding. The satiety center in the ventromedial nucleus releases POMC (to α-MSH and β-endorphin), CART, and GLP-1 to suppress feeding.

What is the key idea of hypothalamic feeding control, and what do anti-obesity drugs do?

The hunger center drives feeding and the satiety center inhibits it. Anti-obesity drugs push the balance toward satiety.

Which GI hormone starts hunger, and where is it released?

Ghrelin, released from the empty stomach. It activates the hunger center, and the sight of food alone can trigger it.

Which GI signals produce fullness, and where are they released?

CCK, PYY, GLP-1, and insulin, released from the small intestine after food intake and digestion. They act on the satiety center.

What does leptin do, and where is it released?

Leptin is released from adipose tissue and signals the satiety center to release POMC and CART.

What is leptin resistance in obesity?

Increased adiposity raises leptin, but the hunger center stays driven by excess intake, so the satiety signal does not stop eating.

What are the three bariatric surgeries?

Adjustable gastric band (AGB), Roux-en-Y gastric bypass (RYGB), and vertical sleeve gastrectomy (VSG)

Why does bariatric surgery reduce calcium absorption?

The stomach area decreases, so stomach pH rises. Calcium carbonate needs acid to dissolve, so calcium absorption falls.

Why does bariatric surgery reduce iron absorption?

Higher stomach pH impairs conversion of Fe³⁺ to Fe²⁺, so less iron is absorbed.

Why does bariatric surgery reduce fat-soluble vitamin absorption?

Food and dietary fat intake decrease, so micronutrients and fat-soluble vitamins A, D, E, and K are absorbed less.

Why does RYGB reduce iron, vitamin, and micronutrient absorption?

RYGB bypasses the duodenum, which is the main absorption site for these nutrients.

How does bariatric surgery change absorption of enteric-coated drugs?

Higher stomach pH can cause enteric-coated drugs designed for the basic intestinal pH to release in the stomach.

How does RYGB affect extended-release drug absorption?

Bypassing the duodenum reduces absorption surface area, especially for extended-release drugs.

How strong is the clinical evidence for bariatric drug absorption changes?

Sparse, and it varies by drug.

What are the indications for anti-obesity drugs?

Lifestyle intervention (diet, exercise, surgery) is first line. Pharmacotherapy is an adjunct for BMI over 30, or BMI 27 to 29 with at least one coexisting condition.

Which anti-obesity drugs are peripherally acting and used long term?

Orlistat, semaglutide (Wegovy), orforglipron (Foundayo), and tirzepatide (Zepbound)

Which anti-obesity drugs are centrally acting and used long term?

Phentermine-topiramate (Qsymia) and bupropion-naltrexone (Contrave)

Which anti-obesity drug is short-term only?

Phentermine

What is orlistat's molecular target, and what is its outcome?

Intestinal gastric and pancreatic lipases, inhibited by acylation of Ser152. Fat digestion is blocked, so triglycerides are not absorbed and cholesterol absorption is also reduced. Calories are lost in stool.

What are the common orlistat side effects?

GI complaints in about 80% of patients, including oily spotting, soft stools, abdominal pain or colic, flatulence, fecal urgency, or incontinence

Why does severe diarrhea matter with orlistat?

It can reduce absorption of oral contraceptives, fat-soluble vitamins A, D, E, K, and β-carotene. Patients need a vitamin supplement, and backup contraception if diarrhea is severe.

What is the molecular target of GLP-1 agonists, and what is the difference in tirzepatide?

GLP-1 receptors in the gut, hypothalamus, and pancreas. Tirzepatide is a dual agonist that also activates GIP receptors.

What are the GLP-1 agonists' effects in the gut, hypothalamus, and pancreas?

Gut: delayed gastric emptying, so fullness lasts longer. Hypothalamus: appetite suppression. Pancreas: increased insulin and decreased glucagon, glucose-dependent.

What are the forms of semaglutide, orforglipron, and tirzepatide?

Semaglutide SQ (Wegovy) is a peptide. Orforglipron oral (Foundayo) is a non-peptide small molecule. Tirzepatide SQ (Zepbound) is a GLP-1/GIP dual agonist peptide.

How do GLP-1 agonists reduce obesity?

Delayed gastric emptying and central appetite suppression together lower total calorie intake.

How does a GLP-1 agonist relate to natural physiology?

It mimics GLP-1, the natural satiety hormone released from the small intestine.

Beyond the slides, what GI side effects do GLP-1 agonists cause, and how are they managed?

Nausea, vomiting, and diarrhea are common, so doses are titrated slowly.

Which drugs reduce oral contraceptive efficacy during dose titration, and for how long?

Tirzepatide and orforglipron, during the first 4 weeks of titration

What is phentermine's molecular target and outcome?

Norepinephrine and dopamine release and reuptake (sympathomimetic). It enhances NE and DA signaling in the hypothalamus, suppressing appetite.

How does phentermine compare with amphetamine?

Structurally similar, but with less CNS stimulation and lower abuse potential

What are phentermine's limits?

Short-term use only because of cardiovascular effects and tolerance. Beyond the slides, it can raise heart rate and blood pressure.

What are topiramate's proposed mechanisms for reducing appetite?

Blocks voltage-gated Na⁺ channels, acts on L-type Ca²⁺ channels, potentiates GABA at a site distinct from benzodiazepine or barbiturate sites, and depresses kainate action on glutamate receptors. The exact mechanism is unknown.

How does Qsymia reduce obesity?

Phentermine gives central appetite suppression, and topiramate adds satiety through GABA and glutamate modulation. Both act centrally.

What is the key safety warning for Qsymia?

Teratogenic, so it must not be used in pregnancy and requires contraception counseling (beyond the slides)

What are bupropion's molecular target and effects in Contrave?

Inhibits neuronal reuptake of dopamine and noradrenaline. This raises DA and NE in the arcuate nucleus and stimulates POMC neurons to release α-MSH and β-endorphin.

What is naltrexone's target and effect in Contrave?

Opioid antagonist at presynaptic mu-opioid receptors on POMC neurons. It blocks endorphin negative feedback, so POMC neurons keep firing.

How does Contrave reduce obesity?

Bupropion increases the POMC signal and naltrexone removes the endorphin brake. α-MSH then acts on MC4 receptors to suppress appetite.

What are the Contrave safety contraindications (beyond the slides)?

Bupropion is contraindicated in seizure disorders or abrupt alcohol or benzodiazepine withdrawal because it lowers the seizure threshold. Naltrexone is contraindicated in patients on opioid analgesics.

What peptides does POMC produce?

α-MSH (appetite suppression via MC4R), ACTH, β-endorphin (the naltrexone feedback target), β-lipotropin, γ-MSH, and CLIP

Which drugs act through the POMC pathway, and which act outside it?

Bupropion-naltrexone acts through POMC, α-MSH, and β-endorphin. Orlistat and GLP-1 agonists act outside this pathway, in the gut and at the GLP-1 receptor.

Which drug has a vitamin absorption concern, and why?

Orlistat, because fat malabsorption also reduces absorption of fat-soluble vitamins A, D, E, and K

How do the anti-obesity drugs compare on site of action and main lever?

Orlistat acts in the gut lumen by blocking fat digestion. GLP-1 agonists act in the gut and hypothalamus by slowing gastric emptying and reducing appetite. Phentermine-topiramate acts in the hypothalamus through NE, DA, and GABA. Bupropion-naltrexone acts in the hypothalamus through DA, NE, and POMC. All four reduce calorie intake or absorption over the long term.

What causes bariatric surgery to reduce oral contraceptive effectiveness?

Severe diarrhea from orlistat can reduce oral contraceptive effectiveness (the other mechanism is covered by the orlistat card)